Eyelet reinforcement at the tissue-suture interface

ABSTRACT

The invention relates to a method of strengthening a tissue against the force of a suture by forming a reinforced eyelet in the tissue. Such an eyelet can be formed by any means that results in strengthening or reinforcement of a tissue against the tensile force of a suture. A reinforced eyelet can be formed via the physical attachment of a strengthening means to a tissue or by contacting a tissue with an eyelet-forming agent. Also described are sutures and kits for use with the method of reinforcing a tissue by forming a reinforced eyelet.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) of U.S.provisional application serial No. 60/325,256, filed Sep. 27, 2001.

FIELD OF THE INVENTION

[0002] The invention is related to methods for repairing tissue, and inparticular is related to methods of tissue repair that involve theformation of a reinforced eyelet.

BACKGROUND

[0003] Tendon injuries are a difficult, serious and frustrating problem.Conservative treatment has little, if any, chance of restoring activemotion in the affected area. Even after surgical repair, full motion isusually not achieved. Permanent loss of motion, joint contractures,weakness, and stiffness often are unavoidable, despite optimal care.Scar tissue can glue together moving surfaces within the tendon sheath,resulting in adhesions and limited motion. See, Tsuge et al. (1977) J.Hand Surg.—[Am.] 2:436-40; Strickland (1987) Orthop. Rev. 16:137-53; andManske et al. (1985) Hand Clin. 1:25-34. Repeat surgery can be requiredto release scar tissue, place tendon grafts, or for other reconstructiveprocedures. Postoperative therapy includes splinting and physicaltherapy. Good patient cooperation with such postoperative therapy isessential to obtaining the best possible result. See, Kleinert and Cash(1985) Instructional Course Lectures 34:361-72; Can et al. (1992) J.Hand Surg.—[Am.] 17:1133-9; and Aoki et al. (1997) J. Hand Surg.—[Am.]22:107-14. In order to permit mobilization immediately after tendonrepair, strong suture techniques are necessary to maintain alignment ofthe lacerated tendon ends until healing occurs. See, Tsuge et al. (1975)Hand 7:250-5; Becker (1978) Hand 10:37-47; Lee (1990) J. Hand Surg.15A:953-958; and Winters et al. (1997) Annales de Chirurgie de la Mainet du Membre Superieur 16:229-34. Excessive loading of the repairedtendon can lead to gap formation or even rupture of the repair. See,Abrahamsson (1991) Scand. J. Plast. Reconstr. Surg. Hand Surg.,Supplementum 23:1-51; Silfverskiold et al. (1992) J. Hand Surg.—[Am.]17:539-46; and Gelberman et al. (1999) J. Bone Joint Surg.—[Am.]81:975-82. Although numerous suture techniques and various suturematerials have been well studied, achieving adequate suture strengthremains a surgical challenge due to the small surface area of thetendon. While multiple suture strands can significantly increase thestrength of the repair, they also can increase the tendon volume at therepair site. See, Becker (1978) Hand 10:37-47; Savage and Risitano(1989) J. Hand Surg.—[Brit.] 14:396-9; and Winters et al. (1998) J. HandSurg.—[Am.] 23:97-104. Such increased volume can jeopardize tendongliding during postoperative therapy due to increased glidingresistance. See, Zhao et al. (1999) Transact. Orthop. Res. Soc. 24:120.A reduction in tendon gliding then can result in increased adhesionformation.

SUMMARY

[0004] The present invention relates generally to the observation thatthe formation of a reinforced eyelet in tissue increases the holdingstrength at a tissue-suture interface. A reinforced eyelet can prevent asuture from cutting through the tissue, so that the tendonsutureinterface gripping strength increases. Increased gripping strength canprevent gap formation in the sutured tissue and rupture of the surgicalrepair.

[0005] In one aspect, the invention features a method of strengthening atissue against the force of a suture. The method can involve reinforcingan eyelet in the tissue. An eyelet can be reinforced before passing asuture through the eyelet, coincident with passing a suture through thetissue, or after passing a suture through the tissue. The tissue can bea tendon (e.g., a flexor tendon). The tissue can be a ligament. Aneyelet can be reinforced biologically, e.g., by a collagen cross-linkingagent such as a carbodiimide. Alternatively, an eyelet can be reinforcedchemically, e.g., by a chemical bonding agent such as a cyanoacrylateglue.

[0006] In another aspect, the invention features an apparatus for theapplication of an eyelet-reinforcing agent to a tissue. The inventionalso features a suture material having an eyelet-reinforcing agentassociated therewith.

[0007] In yet another aspect, the invention features a kit. The kit cancontain a suture material and an eyelet-reinforcing agent.Alternatively, the kit can contain a suture material having aneyelet-reinforcing agent associated therewith. In another embodiment,the kit can contain an eyelet-reinforcing agent.

[0008] The invention also features an isolated tendon containing areinforced eyelet.

[0009] In still another aspect, the invention features a method fortesting the ability of a compound to reinforce an eyelet. The method caninvolve: (a) mounting a tissue on a tensiometer, the tissue having thecompound applied at the site of an eyelet in the tissue; (b) applyingtensile force to a suture loop passing through the eyelet; and (c)measuring the tensile force at which the suture loop is pulled from thetissue.

[0010] Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods and examples are illustrative only and not intendedto be limiting.

[0011] Other features and advantages of the invention will be apparentfrom the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 is a graph plotting the stiffness of EDC-treated (solidline) and untreated (dashed line) tendons. (N=Newtons; mm=millimeters)

[0013]FIG. 2 is a schematic representation of a method for measuringtendon-suture strength using an MTS servohydraulic testing machine.Suture pullout force is measured by pulling on the single loop of thesuture.

[0014]FIG. 3 is a graph plotting the strength of EDC-treated (solidline) and untreated (dashed line) tendons.

[0015]FIG. 4A is a representative cross-sectional drawing of an eyeletin a tendon. FIG. 4B is a representative cross-sectional drawing of theeyelet depicted in FIG. 4A after reinforcement. The stippled portionrepresents the reinforcement surrounding the eyelet.

[0016]FIG. 5 is a graph plotting the average maximum failure force of asingle suture loop in tendons containing an eyelet reinforced with EDCcompared to the average maximum failure force of a single suture loop inuntreated tendons. Ten tendons were tested in each group.

[0017]FIG. 6 is graph plotting the average maximum failure force of asingle suture loop in tendons containing an eyelet reinforced by localglue injection compared to the average maximum failure force of a singlesuture loop in untreated tendons. Four tendons were tested in eachgroup.

DETAILED DESCRIPTION

[0018] The invention is based on the discovery that forming a reinforcedeyelet in a tissue increases the holding strength of the tissue at atissue-suture interface. The reinforced eyelet prevents a suture frommigrating into the tissue or tearing through the tissue. Gap formationin the sutured tissue and rupture of the surgical repair is minimized oreven prevented. This method for reinforcing the edges of a suture holein tissue against the tensile force of the suture can be used in anyprocedure in which soft tissue is sutured. Such tissues include, but arenot limited to, tendon, ligament, skin, and muscle. The use of such areinforcing eyelet in surgical tissue repair has many benefits,including increased suture gripping strength without the use of multiplestitches or locking loops. As a result, the complexity of surgicalstitching procedures is decreased. With the use of less complexstitching, the mass of the repaired site is reduced. This allows lessrestricted movement and increased circulation, promoting more rapidhealing and decreased adhesion formation.

[0019] The model presented is for tendon repair, as this is a commontype of repair that fails by suture pullout. However, the concept isapplicable to any type of soft tissue suture repair.

[0020] Eyelet Formation and Reinforcement

[0021] As used herein, an “eyelet” refers to a hole through a tissue(e.g., a tendon). An eyelet can be formed by, for example, inserting aneedle through a tissue. A “reinforced eyelet” refers to an eyelet thathas been strengthened (e.g., biologically or chemically); the edges of areinforced eyelet typically are stiffer and/or stronger than the edgesof an eyelet that has not been reinforced. A suture placed through areinforced eyelet can be less likely to tear the tissue surrounding theeyelet than a suture placed through an eyelet that has not beenreinforced.

[0022] There are a number of means by which a tissue can be reinforcedagainst the tensile force of a suture. For example, an eyelet can bereinforced by the physical attachment of a strengthening means, such asa metal or plastic grommet, to a tissue. An eyelet also can bereinforced by contacting a tissue with an eyelet-reinforcing agent. Suchan agent can act either by biologically modifying the tissue itself, orby chemically attaching a bonding agent to the tissue. For example, across-linking agent can function as a biological eyelet-reinforcingagent, while a bonding agent such as a glue can function as a chemicaleyelet-reinforcing agent. Any means known in the art for applying anagent to a tissue can be used to apply an eyelet-reinforcing agent. Forexample, an eyelet-reinforcing agent can be spotted on a tissue with,e.g., a needle, stylus, or probe, and allowed to diffuse into thetissue. An eyelet-reinforcing agent can be administered as a bead ofliquid present on the tip of a needle as it is passed through a tissue.An eyelet-reinforcing agent can be directly administered into a tissueby, for example, injection through a needle. In another means ofdelivery, an eyelet-reinforcing agent can be pre-coated on a needle orcoated or embedded on a suture material. In this case, theeyelet-reinforcing agent is delivered to the tissue by the act ofstitching or suturing. It is noted that such procedures also can be usedwith surgical staples. In these embodiments, a reinforced eyelet can beformed prior to insertion of the staple, or an eyelet-reinforcing agentcan be pre-coated on a surgical staple and thus be delivered to thetissue upon the act of stapling.

[0023] Tendon Repair

[0024] While the use of a reinforced eyelet is applicable to any type ofsoft tissue suture repair, the use of reinforced eyelets in tendonrepair is presented as a model system, as this is a common type ofrepair that frequently fails because of suture pullout. The weakestportion of the repaired tendon is the suture-tendon interface. Thetypical failure mode is of the suture cutting through the tendon causinga gap to form, followed by complete rupture. Some investigators havesuggested using multiple or locking loops to increase the suturegripping strength. See, Lin et al. (1988) J. Hand Surg.—[Am.] 13:553-8;Mashadi and Amis (1991) J. Hand Surg. [Brit.] 16:35-9; and Hatanaka andManske (1999) J. Hand Surg.—[Am.] 24:751-60. However, these procedurescan jeopardize the intrinsic blood supply of the tendon, damage thetissues, complicate surgical performance and increase the tendon glidingresistance. See, Lundborg et al. (1977) J. Hand Surg.—[Am.] 2:417-27 andManske et al. (1984) J. Bone Joint Surg.—[Am.] 66:385-96. The idealsuture construct will have a combination of high strength and lowgliding resistance. The present invention provides methods forreinforcing an eyelet in a tissue through which a suture passes, thusincreasing the suture gripping strength without the use of multiple orlocking loops, and providing a combination of high strength and lowgliding resistance.

[0025] Structure of Collagen

[0026] Collagens are insoluble, extracellular glycoproteins that arefound in all animals. Collagen is the most abundant protein in the humanbody and is an essential structural component of all connective tissues,such as cartilage, bone, tendons, ligaments, fascia and skin. The basicunit of collagen is a polypeptide consisting of the repeating sequence(glycine (Gly)-X-Y)_(n), where X is often proline and Y is oftenhydroxyproline. In a collagen molecule, three separate polypeptidechains, each rich in proline and containing a glycine at every thirdresidue, are wound around one another to generate a left-handed triplehelix. These collagen molecules are packed together into fibrils. Afterthe fibrils form in the extracellular space, they are greatlystrengthened by the formation of covalent cross-links between lysineresidues of the constituent collagen molecules. The types of covalentbonds involved are found only in collagen and elastin, giving thesemolecules enormous tensile strength. If such cross-linking is inhibited,the tensile strength of the fibrils is drastically reduced, collagenoustissues become fragile, and structures such as skin, tendons, and bloodvessels tend to tear. See Molecular Biology of the Cell, 3^(rd) Edition,Alberts et al., eds., 1994, Garland Publishing, Inc. (New York, N.Y.),pages 115-116 and 978-984.

[0027] Cross-Linking Agents

[0028] In one embodiment, the present invention serves to increasesuture-holding strength in a tendon and other collagenous tissue byincreasing the extent of cross-linking between collagen molecules.Cross-linking the collagen fibers of a tendon to reinforce an eyelet canbe accomplished by a number of methods. Cross-linking agents can beselected so as to produce a biocompatible material and can include,without limitation, UV irradiation and chemical cross-linking agents.Suitable chemical cross-linking agents include, for example, acyl-azide,hexamethylene diisocyanate, bisimidates, glyoxal, polyglycerolpolyglycidyl ether, adipyl chloride, ribose and other sugars,carbodiimides, and aldehydes such as glutaraldehyde, formaldehyde, andother aldehydes. See, e.g., WO 85/00511.

[0029] Carbodiimides include, without limitation, monocarbodiimides andbiscarbodiimides. Monocarbodiimides include EDC,cyclohexyl-B-(N-methylmorpholino) ethylcarbodiimide p-toluene-sulfonate(CMC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide(ETC), for example. Biscarbodiimides includephenylenebis-(ethyl)-carbodiimide, and 1,6-hexamethylenebis(ethylcarbodiimide), for example. Carbodiimides such as EDC can activatecarboxyl groups on a collagen molecule, which then can form syntheticpeptide bonds with adjacent amino groups, releasing urea. EDC is awell-known monocarbodiimide cross-linking agent, and has been approvedfor use in human patients.

[0030] Bonding Agents

[0031] A bonding agent also can serve as an eyelet-reinforcing agent.Suitable bonding agents include, for example, materials that rapidlypolymerize when applied to the surface of biological tissue. Suchbonding materials include, without limitation, cyanoacrylate-basedadhesives, e.g., Eastman 910 and Histoacryl Blue (based on methyl- andbutyl 2-cyanoacrylate, respectively), familiar domestic adhesives suchas super glue and “CrazyGlue™”, and surgical adhesives. Other suitablebonding agents include fibrin glue and the polymerized compliant tissuesealants discussed in U.S. Pat. No. 6,217,894, for example. Fibrin glueis composed of fibrinogen, blood coagulation factor XIII, and thrombin.See, e.g., U.S. Pat. Nos. 4,627,879, 5,185,001, 5,226,877, 5,290,552,5,510,102 and 6,083,383. In general, any bonding material can besuitable as a bonding agent provided that it can bond to the biologicaltissue in the region of the eyelet and can provide the requisite tensilestrength.

[0032] Suture Material

[0033] Suture materials include surgical silk and any other materialthat can be passed through a tissue during tissue repair (e.g., suturingthread, clips, and staples). To facilitate the delivery of aneyelet-reinforcing agent to the tissue to be repaired, theeyelet-reinforcing agent can be pre-spotted on the suture material indefined positions, or the entire suture material can be pre-coated orembedded with an eyelet-forming agent. In this case, theeyelet-reinforcing agent can be delivered to the tissue surrounding thesuture during the act of suturing. The eyelet-reinforcing agent can bepre-coated or embedded on the suture material along with atemperature-sensitive carrier. Such a carrier can remain in a solidstate at a temperature less than physiological body temperatures and canliquefy at physiological body temperature, thus facilitating the contactof the eyelet-reinforcing agent with the tissue. An example of such athermosensitive carrier is a poly(N-isopropylacrylamide) hydrogel. See,e.g., Gutowska et al. (1995) J. Biomed. Mater. Res. 29(7):811-21; Makinoet al. (2001) Colloids Surf. B. Biointerfaces 29(4):341-346; and Uludaget al. (2001) Biotechnol. Bioeng. 73(6):510-21.

[0034] Kits/Apparatus

[0035] In other embodiments, the invention provides kits and articles ofmanufacture useful for reinforcing an eyelet in a tissue. The kit orarticle of manufacture can contain suture material and/or aneyelet-reinforcing agent. The suture material can be spotted with aneyelet-reinforcing agent at defined positions, or the entire suturematerial can be pre-coated or embedded with the eyelet-reinforcingagent. The kit or article of manufacture also can contain an object(e.g., a needle) suitable for forming an eyelet, and in someembodiments, the object can be pre-spotted or pre-coated with aneyelet-reinforcing agent. When the object is a needle with a bore, forexample, the eyelet-reinforcing agent can be pre-coated on the outsidesurface of the needle and/or contained within the bore.

[0036] The kit or article of manufacture can contain additionalcomponents desirable from a commercial or user standpoint. Components ofthe kits and articles of manufacture may or may not be sterile. A labelor packaging insert indicating the components are to be used forstrengthening a tissue against the force of a suture by forming areinforced eyelet in the tissue with an eyelet-reinforcing agent canaccompany the kit or article of manufacture.

[0037] The invention also provides an article of manufacture useful forreinforcing an eyelet in a tissue.

[0038] The invention also provides an apparatus that can be used in theprocess of reinforcing an eyelet in a tissue. Such an apparatus can be,for example, a surgical apparatus to facilitate the reinforcement of aneyelet in a tissue, the delivery of an eyelet-reinforcing agent to atissue surface, or the use of eyelet-tendon repair techniques inarthroscopic surgical procedures.

[0039] Isolated Tendons

[0040] Eyelet-reinforcing agents can be used to form reinforced eyeletsin isolated tendons. Tendons can be obtained from human cadavers or fromother species. Isolated tendons, after formation of reinforced eyelets,can be packaged and stored by methods known in the art, such that theyare readily available for use in surgical repair procedures.

[0041] The invention will be further described in the followingexamples, which do not limit the scope of the invention described in theclaims.

EXAMPLES Example 1 Cross-Linking a Tendon with EDC

[0042] EDC is a cross-linking activating reagent that can couple thecarboxyl groups of one collagen molecule to the amino groups of anothercollagen molecule by forming covalent cross-links. Tendons cross-linkedwith EDC were much stiffer than untreated tendons. This increase intendon stiffness was confirmed by studying the mechanical properties ofnormal and EDC-treated tendons. Each tendon was mounted on atensiometer, specifically a model 810 MTS servohydraulic testing machine(MTS, Eden Prairie, Minn.) using specially designed clamps. The tendongage length was approximately 30 mm. A differential variable reluctancetransducer (DVRT; MicroStrain, Burlington, Vt.) was attached to a middleportion of the tendon to measure localized tendon elongation. As shownin FIG. 1, the stiffness of a tendon cross-linked with EDC was greaterthan the stiffness of an untreated tendon. The non-linear portion of theloading curve (toe region) was reduced compared to the normal tendon.Under a 50 Newton load, the tendon within the DVRT portion was elongatedabout 0.5 mm. Under the same load, the untreated tendon was stretched1.5 mm, a length three times greater than the tendon treated with EDC.The results indicate that EDC cross-linking yields a tendon that doesnot stretch easily.

Example 2 Measuring Single Suture Loop Failure in EDC-Treated Tendon

[0043] Single loop sutures were passed through both an EDC-treatedtendon and an untreated tendon and gripping strength was tested. Tendonspecimens were mounted on an MTS servohydraulic testing machine withclamps to secure the tendon, as depicted in FIG. 2. The suture loop washooked to the movable wheel of the testing machine, and the tendon wasdistracted at a rate of 20 mm/min until complete suture pulloutoccurred. Data on tensile force and displacement were collected at arate of 20 Hz for both EDC cross-linked and untreated tendons. Thefailure mode of EDC cross-linked tendon was suture breakage at the peakload. However, in the untreated tendons the failure mode was the suturecutting through the tendon until the suture loop pulled out. Theseresults, shown in FIG. 3, indicate that suture strength was dramaticallyincreased by EDC cross-linking of the tendon.

Example 3 Measuring Single Suture Loop Failure in Eyelets Formed withEDC

[0044] Due to undesirable changes in the overall physiochemicalproperties of the treated tendon, EDC treatment of an entire tendon isnot a practical option for use in tendon repair procedures. Therefore,EDC cross-linking was limited to a region of the tendon immediatelyadjacent to the suture, in order form a locally reinforced eyelet in thetendon. Such a reinforced eyelet is represented in FIG. 4. Ten flexortendons from canine forepaws were obtained for testing of thereinforcement. To eliminate the effect of tendon size, each tendon wasdivided into two pieces. One half of each tendon served as an untreatedcontrol, and the other half of the tendon was in the experimental group.A 22-gauge needle was transversely inserted through the tendon 5 mm fromthe tendon end. Approximately 10 μl of 10% EDC solution was injectedinto the tendon upon insertion of the needle, so that the EDC wasdeposited around the needle hole to reinforce the eyelet. 4/0 nylonsuture (Ethicon, Somerville, N.J.) was passed through the needle hole,and a single loop suture was placed after the needle was withdrawn. Forthe control group, saline was injected instead of EDC.

[0045] After at least one hour (generally after about one to about sixhours), each tendon specimen was mounted on an MTS servohydraulictesting machine with clamps to secure the tendon. The suture loop washooked to the movable wheel and the tendon was distracted at a rate of20 mm/min until complete suture pullout occurred. Tensile force anddisplacement data were collected at a rate of 20 Hz. The failure mode inall untreated tendons and some of the tendons with EDC-eyelets was dueto the suture cutting through the tendon. Three tendons in theEDC-eyelet group failed due to suture rupture. As shown in FIG. 5, theaverage maximum force in the EDC-treated group (11.5±2.4 Newtons) wassignificantly greater than that of the untreated group (6.2±3.3 Newtons;p<0.001). These results indicate that a reinforced eyelet can withstanda greater force than an unreinforced eyelet, for example, a force thatis at least 1.5 times greater (e.g., 1.5 to 2.5 times greater, 1.5 to3.0 times greater, 2.0 to 3.0 times greater, 1.5 to 4.0 times greater,or more than 4.0 times greater).

Example 4 Measuring Single Suture Loop Failure in Eyelets Formed withSuperglue

[0046] In a further experiment, super glue was applied to tendons toform chemically reinforced eyelets. Three canine flexor digitorumprofundus tendons were tested. To eliminate the effect of tendon size,each tendon was divided into two pieces. One half of each tendon servedas an untreated control, and the other half of the tendon was in theexperimental group. By the same procedures used in Example 3, a 22-gaugeneedle was used to apply super glue to each tendon to form a reinforcedeyelet. A 4/0 nylon suture was then passed through the needle hole, anda single loop suture was placed after the needle was withdrawn. For thecontrol group, saline was injected instead of EDC. Each tendon specimenwas mounted on an MTS servohydraulic testing machine with clamps tosecure the tendon. The suture loop was hooked to the movable wheel andthe tendon was distracted at a rate of 20 mm/min until complete suturepullout occurred. Tensile force and displacement data were collected ata rate of 20 Hz. The average maximum force in the super glue treatedgroup was 12.2 Newtons, while that of the untreated group was 4.2Newtons (see FIG. 6).

Example 5 Effectiveness of the Use of Reinforced Eyelets in TendonRepair

[0047] The effect of a reinforced eyelet on gliding resistance in arepaired tendon can be tested in a canine flexor tendon model usingmethods such as those outlined in Momose et al. (2000) Appl. Biomater.53(6):806-11.

[0048] The repair of partially lacerated flexor tendon injuries in zone2 continues to present a challenge to hand surgeons. The repair itselfoften is detrimental to the biomechanical performance of the flexortendon, with the additional insult to the tendon caused by sutureplacement further weakening the overall structure of the tendon.Adhesion formation, suture rupture, and suture locking on the pulleyedge are possible consequences of a poor repair. See, Zobitz et al.(2000) J. Biomech. Eng. 122:604. The effectiveness of the use of areinforced eyelet for repairing partially lacerated tendons can bestudied in the partial laceration canine model. Using the methods ofZobitz et al., repair strength (failure load and gap formation) ismeasured in tendons repaired with reinforced eyelets, and is compared torepair strength in tendons repaired using conventional surgicaltechniques.

[0049] The in vivo effects of reinforced eyelets in surgical tendonrepair are determined using methods such as those of Winter et al. andGelberman et al. For example, tendon strength, gliding function, andrange of motion are measured in transected canine flexor tendonsrepaired in vivo. See, Winters et al. (1998) supra, and Gelberman supra.The compatibility of reinforced eyelets with various suturing techniquesis tested by various methods, including those set forth in Lin et al.supra, Winters et al. (1998) supra, Hatanaka and Manske supra, andZobitz et al. supra.

Other Embodiments

[0050] It is to be understood that while the invention has beendescribed in conjunction with the detailed description thereof, theforegoing description is intended to illustrate and not to limit thescope of the invention, which is defined by the scope of the appendedclaims. Other aspects, advantages and modifications are within the scopeof the following claims.

What is claimed is:
 1. A method of strengthening a tissue against theforce of a suture, said method comprising reinforcing an eyelet in saidtissue.
 2. The method of claim 1, wherein said eyelet is reinforcedbefore passing a suture through said eyelet.
 3. The method of claim 1,wherein said eyelet is reinforced coincident with passing a suturethrough said tissue.
 4. The method of claim 1, wherein said eyelet isreinforced after passing a suture through said tissue.
 5. The method ofclaim 1, wherein said tissue is a tendon.
 6. The method of claim 5,wherein said tendon is a flexor tendon.
 7. The method of claim 1,wherein said tissue is a ligament.
 8. The method of claim 1, whereinsaid eyelet is reinforced biologically.
 9. The method of claim 8 whereinsaid eyelet is reinforced by a collagen cross-linking agent.
 10. Themethod of claim 9 wherein said cross-linking agent is a carbodiimide.11. The method of claim 10 wherein said cross-linking agent is1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.
 12. Themethod of claim 1, wherein said eyelet is reinforced chemically.
 13. Themethod of claim 12, wherein said eyelet is reinforced by a chemicalbonding agent.
 14. The method of claim 13 wherein said bonding agent isa cyanoacrylate glue.
 15. An apparatus for the application of aneyelet-reinforcing agent to a tissue.
 16. A suture material comprisingan eyelet-reinforcing agent.
 17. The suture material of claim 16,wherein said eyelet-reinforcing agent is a cross-linking agent.
 18. Thesuture material of claim 16, wherein said eyelet-reinforcing agent is abonding agent.
 19. A kit comprising a suture material and aneyelet-reinforcing agent.